The present invention relates to an improved process for the production of 5-nitro-acet-2,4-xylidine. It is the object of this invention to provide a process for the manufacture of 5-nitro-acet-2,4-xylidine whereby the same is obtained in good yield. Another object is to provide a process in which an acceptably low amount of 6-nitro-acet-2,4-xylidine is produced. Another object is to provide a process in which relatively large batch sizes can be made and in which significant amounts of sulfonation side-reaction can be avoided.
The compound, 5-amino-acet-2,4-xylidine, is known in the art and is used as an intermediate for the preparation of 5-acetamido-2,4-dimethyl-trifluoro-methane-sulfonanilide (see, e.g., U.S. Pat. Nos. 3,894,078 and 4,013,444). In general, 5-amino-acet-2,4-xylidine can be produced by catalytically hydrogenating 5-nitro-acet-2,4-xylidine. The 5-nitro-acet-2,4-xylidine is generally produced by first dissolving acet-2,4-xylidine in a concentrated aqueous sulfuric acid solution (i.e., 96% sulfuric acid) and thereafter nitrating with a mixed solid. The 5-nitro-acet-2,4-xylidine is then recovered. In general, the 5-nitro isomer is not recovered in pure form but also in mixture with the 3-nitro and 6-nitro isomers. The presence of 6-isomer ultimately can lead to difficulties of purification of 5-acetamino-2,4-dimethyl-trifluoromethylsulfonanilide and therefore is undesirable.
The above procedure, making use of 96% sulfuric acid, cannot be used for relatively large batch sizes due to the acceptable amounts of sulfonation side-reaction of acet-2,4-acetxylidine which takes place due primarily to the long charging times. Thus, for example, at least 15% by weight of acet-2,4-xylidine undergoes sulfonation reaction in 97.5% sulfuric acid at 25.degree. C. in only 1 hour, and around 5% undergoes sulfonation in 95% sulfuric acid in only 5 hours. The use of dilute sulfuric acid as reaction medium effectively diminishes the rate of sulfonation; thus, for example, only around 0.5% acet-2,4-xylidine undergoes sulfionation in 90% sulfuric acid in as many as 29 hours.
However, according to the prior art, the concentration of sulfuric acid as solvent has a dramatic effect on the regioselectivity of the nitration reaction of aromatic acetylamino-compounds. Compare for example, U.S. Pat. No. 4,139,558 and U.S. Pat. Nos. 1,963,598, 1,963,597 and 2,128,511 in which a nitration reaction in 96% sulfuric acid leads to substitution meta to the acetylamino group, while a nitration reaction in 80% sulfuric acid leads to substitution ortho to the acetylamino-group. Therefore, based on the prior art, and based on the fact that nitration of acet-2,4-xylidine in nitric acid alone gave substitution ortho to the acetylamino group affording 6-nitroacet-2,4-xylidine, it would have been expected that nitration in 90% sulfuric acid would have given at least large proportions of product of substitution ortho to the acetylamino group.
Contrary to the expected results, the present invention is based on the surprising discovery that nitration of acet-2,4-xylidine in 90% sulfuric acid affords about 96% specific substitution meta to the acetylamino group. The remarkable meta selectivity in nitrating acet-2,4-xylidine in 90% sulfuric acid cannot be attributed to the directing influence of the methyl groups since the opposite selectivity is observed by nitrating in aqueous nitric acid (sp. gr. 1.42) yielding only 6-nitro-acet-2,4-xylidine. The greater influence of the acetylamino group than the methyl group in determining the position of substitution is also illustrated by the example of U.S. Pat. No. 2,128,511 in which N-acetyl-4-toluidine is nitrated in a relatively high sulfuric acid concentration, say about 80%, in which the substitution is predominantly ortho to the acetylamino group affording N-acetyl-3-nitro-toluidine. Thus the use of 90% sulfuric acid as reaction solvent allows a process of a relatively large batch size in which significant amounts of sulfonation side-reaction can be avoided, allows a process in which relatively small amounts of undesirable 6-nitro-acet-2,4-xylidine are formed, and allows a process in which 5-nitro-acet-2,4-xylidine is obtained in good yield.